Oxidation & Reduction Compounds Containing Carbonyl Groups

Chapter 20 Two broad classes of compounds contain the carbonyl group:

• Compounds that have only carbon and hydrogen atoms bonded to the carbonyl.

• Compounds that contain an electronegative atom bonded to the carbonyl. Carbonyl Groups

Carbonyl Group Structure & Polarity General Reactions of Carbonyl Compounds Nucleophilic Addition Nucleophilic Substitution

• Aldehydes and ketones react with nucleophiles to form addition products by a • Carbonyl compounds with two-step process: nucleophilic attack followed by protonation. leaving groups react with nucleophiles to form substitution products by a two-step process: nucleophilic attack, followed by loss of the leaving group.

Comparison of Carbonyl Reaction Types Overview of Oxidation and Reduction

• Nucleophilic addition and nucleophilic acyl substitution involve the same first step - nucleophilic attack on the electrophilic carbonyl carbon to form a tetrahedral intermediate. • The difference between the two reactions is what then happens to the intermediate. • Aldehydes and ketones cannot undergo substitution because they do not have a good leaving group bonded to the newly formed sp3 hybridized carbon. • Carbonyl compounds can be either reactants or products in oxidation–reduction reactions. Reduction of Aldehydes and Ketones Catalytic Hydrogenation of Carbonyls

• The most useful reagents for reducing aldehydes and ketones are the metal hydride reagents. • Catalytic hydrogenation also reduces aldehydes and ketones to 1° and 2°

alcohols, respectively, using H2 and a catalyst.

• Treating an aldehyde or ketone with NaBH4 or LiAlH4, followed by H2O or some other proton source affords an alcohol. The net reaction is the addition of “H2”.

• When a compound contains both a carbonyl group and a carbon–carbon double bond, selective reduction of one functional group can be achieved by proper choice of the reagent.

• A C=C is reduced faster than a C=O with H2 (Pd–C).

• A C=O is readily reduced with NaBH4 and LiAlH4, but a C=C is inert.

Comparison of Carbonyl Reductions Sodium Borohydride Reductions in Synthesis

• Thus, 2-cyclohexenone, which contains both a C=C and a C=O, can be reduced to three different compounds depending upon the reagent used. Stereochemistry of Carbonyl Reduction Enantioselective Carbonyl Reductions

• Selective formation of one enantiomer over another can occur if a chiral reducing agent is used. • A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction. • An example of chiral reducing agents are the enantiomeric CBS reagents, for Corey, Bakshi, and Shibata.

Biological Reductions Mechanism of NADH Reductions • Biological reductions that occur in cells always proceed with complete • The active site of the enzyme binds both the carbonyl substrate and NADH, selectivity, forming a single enantiomer. keeping them in close proximity. • In cells, the reducing agent is NADH. • NADH then donates H:− in much the same way as a hydride reducing agent. • NADH is a coenzyme—an organic molecule that can function only in the presence of the enzyme. Enantioselectivity of NADH Reduction NAD+ —Biological Oxidizing Agent

• The reaction is completely enantioselective. • NAD+, the oxidized form of NADH, is a biological oxidizing agent • For example, reduction of pyruvic acid with NADH catalyzed by lactate dehydrogenase affords a single enantiomer with the S configuration. capable of oxidizing alcohols to carbonyl compounds (it forms • NADH reduces a variety of different carbonyl compounds in biological systems. NADH in the process). • The configuration of the product (R or S) depends on the enzyme used to • NAD+ is synthesized from the vitamin niacin. catalyze the process.

LiAlH4 Reductions LiAlH4 Reductions

• Carboxylic acids are reduced to 1° alcohols with LiAlH4. • Like carboxylic acids, esters and acid chlorides are reduced to 1° alcohols with LiAlH4 followed by aqueous workup. • LiAlH4 is too strong of a reducing agent to stop the reaction at the aldehyde stage, but milder reagents (e.g. NaBH4) are not strong enough to initiate the reaction in the first place.

• The mechanism will be presented in lecture.

20 Other Metal Hydride Reducing Agents Reduction of Esters & Acid Chlorides

• Diisobutylaluminum hydride [(CH3)2CHCH2]2AlH, abbreviated DIBAL-H, has two bulky isobutyl groups which makes this reagent

less reactive than LiAlH4.

• Lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH3)3]3, has three electronegative O atoms bonded to aluminum, which makes

this reagent less nucleophilic than LiAlH4.

• The mechanisms for DIBAL-H and LiAlH(tert-BuO)3 reductions will be presented in lecture.

LiAlH Reduction of Amides 4 LiAlH4 Reduction of Amides

• Unlike the LiAlH4 reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlH4 reduction of amides forms amines.

− • Since NH2 is a very poor leaving group, it is never lost during the reduction, and therefore an amine is formed. Organometallic Reagents

• Li, Mg, and Cu are the most common organometallic metals. • Other metals found in organometallic reagents are Sn, Si, Tl, Al, Ti, and Hg. • General structures of common organometallic reagents are shown:

Reactivity of Common Organometallic Compounds Preparation of Organo-Li/MgX Compounds • Organolithium and Grignard reagents are typically prepared by reaction of an • Organomagnesium reagents are called Grignard reagents. alkyl halide with the corresponding metal. • Since both Li and Mg are very electropositive metals, organolithium (RLi) and • With lithium, the halogen and metal exchange to form the organolithium organomagnesium (RMgX) reagents contain very polar carbon-metal bonds and reagent. are therefore very reactive reagents. • With Mg, the metal inserts in the carbon–halogen bond, forming the Grignard • Organolithium and Grignard reagents have very similar reactivities with organic reagent. compounds.

• Organocopper reagents (R2CuLi), also called organocuprates, have a less polar carbon–metal bond and are therefore less reactive. • Although they contain two R groups bonded to Cu, only one R group is utilized in the reaction. • In organometallic reagents, carbon bears a δ− charge.

Solvent Stabilization of Grignard Reagents Preparation of Organocuprate Compounds Preparation of Lithium Acetylides

• An acid–base reaction can also be used to prepare sp hybridized • Organocuprates are prepared from organolithium reagents by reaction organolithium compounds. with a Cu+ salt, often CuI. • Treatment of a terminal alkyne with CH3Li affords a lithium acetylide. • The equilibrium favors the products because the sp hybridized C–H bond of the terminal alkyne is more acidic than the sp3 hybridized conjugate

acid, CH4, that is formed.

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Acid–Base Reactions of Organometallics & Solvent Limitations Organometallics & Functional Group Transformations

• Organometallic reagents are strong bases that readily abstract a proton from • Reaction of R–M with aldehydes and ketones to afford alcohols water to form hydrocarbons.

Synthesis:

• Reaction of R–M with carboxylic acid derivatives Acid-Base:

• Reaction of R–M with other electrophilic functional groups

• Similar reactions occur with the N–H protons of amines. Nucleophilic Addition of Grignard Reagents Mechanism of Organometallic Addition

• This reaction follows the general mechanism for nucleophilic addition—that is, nucleophilic attack by a carbanion followed by protonation.

• Mechanism 20.6 is shown using R-MgX, but the same steps occur with R-Li reagents and acetylide anions.

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Synthesis of C Juvenile Hormone More Examples of Alcohols Formed by Organometallic Addition 18

• C18 juvenile hormone helps to regulate the complex life cycle of insects.

• Juvenile hormones maintain the juvenile stage of an insect until it is ready for adulthood. • Juvenile hormone mimics have been used to effectively control insect populations. • Application of these synthetic hormones to egg or larva prevents maturation. • Methoprene is used in cattle salt blocks to control hornflies and on dogs and cats to control fleas. Retrosynthetic Analysis of Grignard Products Retrosynthetic Analysis of 3-pentanol

• To determine what carbonyl and Grignard components are needed to prepare a given compound, follow these two steps:

• Note that there is often more than one way to synthesize a 2° alcohol by Grignard addition.

Organometallic Reactions with Esters and Acid Chlorides Organometallic Reactions with Esters and Acid Chlorides

• Both esters and acid chlorides form 3° alcohols when treated with two equivalents of either Grignard or organolithium reagents. Organometallic Reactions with Epoxides Grignard Reaction with CO2

• Grignards react with CO2 to give carboxylic acids after protonation with aqueous acid. • Like other strong nucleophiles, organometallic reagents - RLi, RMgX, and R2CuLi - open epoxide rings to form alcohols. • This reaction is called carboxylation. • In unsymmetrical epoxides, nucleophilic attack occurs at the less-substituted carbon atom. • The carboxylic acid formed has one more carbon atom than the Grignard reagent from which it was prepared.

Mechanism:

Limitations of Organometallic Reagents Use of Protecting Groups

• Addition of organometallic reagents cannot be used with molecules that contain Solving this problem requires a three-step strategy: both a carbonyl group and N–H or O–H bonds. [1] Convert the OH group into another functional group that does not interfere with the desired reaction. This new blocking group is called a protecting group, and the reaction • Carbonyl compounds that also contain N–H or O–H bonds undergo an acid–base that creates it is called protection. reaction with organometallic reagents, not nucleophilic addition. [2] Carry out the desired reaction. [3] Remove the protecting group. This reaction is called deprotection.

Not Formed Preparing Silyl Ethers Synthesis with a Silyl Ether Protecting Group

• tert-butyldimethylsilyl ethers are prepared from alcohols by reaction with tert- • The use of tert-butyldimethylsilyl ether as a protecting group makes butyldimethylsilyl chloride and an amine base, usually imidazole. possible the synthesis of 4-methyl-1,4-pentanediol by a three-step sequence.

• The silyl ether is typically removed with a fluoride salt such as + − tetrabutylammonium fluoride (CH3CH2CH2CH2)4N F .

Organocuprates—a Less Reactive Organometallic Organometallic Reactions with α,β-Unsaturated Carbonyl Compounds

• To form a ketone from a carboxylic acid derivative, a less reactive organometallic • α,β-Unsaturated carbonyl reagent—namely an organocuprate—is needed. compounds are conjugated molecules containing a • Acid chlorides, which have the best leaving group (Cl−) of the carboxylic acid carbonyl group and a C=C derivatives, react with R’ CuLi to give a ketone as the product. 2 separated by a single σ bond. − • Esters, which contain a poorer leaving group ( OR), do not react with R’2CuLi.

• Resonance shows that the carbonyl carbon and the β carbon bear a partial positive charge. α,β-Unsaturated Carbonyl Compounds 1,2 vs. 1,4 - Addition Products

• This means that α,β-unsaturated carbonyl compounds can react with nucleophiles at two different sites.

1,2 vs. 1,4 - Addition Mechanism Synthesis Practice • The steps for the mechanism of 1,2-addition are exactly the same as those for the nucleophilic addition of an aldehyde or a ketone – that is, nucleophilic attack, followed by protonation. • Synthesize 1-methylcyclohexene from cyclohexanone and any • The 1,4 addition mechanism: organic alcohol.

+ R-OH

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